The Geriatric Psychiatry Branch (GPB) has devoted most of its attention to the study of individuals who either have Alzheimer?s disease (AD) or are "at risk" of developing AD. The focus of this clinical research is the identification and quantification of biologic markers (?biomarkers?) of disease that might be used in the diagnosis and clinical monitoring of these subjects. Previously published data has shown that cerebrospinal fluid (CSF) is a major source of information about the biochemistry of AD. In fact, CSF beta-amyloid and tau proteins have been suggested as important "biomarkers" because of their central role in the pathologic definition of the illness at autopsy. In the largest-ever published study comparing a group of mild-to-moderate AD subjects to older controls, we found that CSF beta-amyloid was lower and CSF tau was elevated in the AD compared to controls (Sunderland et al., 2003). This finding was consistent with a meta-analysis of the world literature (Sunderland et al., 2003). We are now examining the CSF levels of beta-amyloid and tau in the "at risk" individuals and finding that when the control subjects are divided by their APOE epsilon 4 allele status, there is a significant difference in beta-amyloid levels between those who are APOE epsilon 4(+) and APOE epsilon 4(-) (Sunderland et al., In press). In the neuroimaging section of the GPB, Dr. Robert Cohen has found with serial measures on MRI scans that the hippocampal volume in the APOE epsilon 4 (+) females decreases faster over time than that of the APOE epsilon 4 (-) females (Cohen et al., 2001). From a cognitive perspective, we are also seeing subtle statistical differences in specific neuropsychological tests within the ?at risk? group according to APOE epsilon 4 genotype (Levy et al., 2004), although the subjects are well within normal range for all the routine clinical variables. Therefore, it appears that even before there is phenotypic evidence of disease, there are individuals who show signs of preclinical change in specific, predicted measures (?biomarkers?) that are characteristic but not necessarily diagnostic of AD. It is for this reason that these subjects are extremely valuable for future study in this longitudinal project.